This application proposes to extend treatment and follow-up in the Women's Health Study, an ongoing randomized, double-blind, placebo-controlled trial evaluating the benefits and risks of low-dose aspirin (100 mg on alternate days), vitamin E (600 IU on alternate days), and beta-carotene (50 mg on alternate days) ina the primary prevention of cardiovascular disease and cancer among approximately 40,000 US female health professionals, aged 45 years and older. The trial utilizes a 2x2x2 factorial design and is conducted entirely by mail using a streamlined, highly cost-efficient study protocol. Average duration of treatment and follow-up is currently 20.3 months, with 87% of randomized participants having at least one year and 47% having at least two years of follow-up. Currently, 90.8% of participants are taking all three study pills, and 93.2% are continuing ot take at least one pill. 98.7% of participants continue to provide complete morbidity data on questionnaires, and mortality follow-up is 99.7%. With continued excellent compliance and follow-up rates, at the conclusion of the proposed extension the trial will have 85-95% power to detect eh most plausible 25-30% benefits of low-dose aspirin, vitamin E, and beta-carotene on risks of the primary trial endpoint of important vascular events. Despite clear evidence of a benefit of low-dose aspirin on risk of a first myocardial infarction in men, no trial data have been collected in apparently healthy women, among whom the benefit-to-risk ratio for aspirin may be less favorable. Further, trial data are inadequate in both men and women on aspirin in primary prevention of stroke and cardiovascular death. As regards vitamin E and beta -carotene, while observational epidemiologic studies have shown that people with high intake of antioxidant vitamins, through diet or supplements, have lower risks of cardiovascular disease, randomized trial data are both lacking and necessary to establish whether the agents themselves are protective or the relationships seen in observational studies are due to uncontrolled or uncontrollable confounding. Thr proposed extension will enable the Women's Health Study to provide definitive tests of these important hypotheses, thereby allowing for the formulation of rational policy recommendations for the general public as well as informed clinical decision-making for individuals.